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DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.

Although central to evolution, the causes of hybrid inviability that drive reproductive isolation are poorly understood. Embryonic lethality occurs when the eggs of the frog X. tropicalis are fertilized with either X. laevis or X. borealis sperm. We observed that distinct subsets of paternal chromosomes failed to assemble functional centromeres, causing their mis-segregation during embryonic cell divisions. Core centromere DNA sequence analysis revealed little conservation among the three species, indicating that epigenetic mechanisms that normally operate to maintain centromere integrity are disrupted on specific paternal chromosomes in hybrids. In vitro reactions combining X. tropicalis egg extract with either X. laevis or X. borealis sperm chromosomes revealed that paternally matched or overexpressed centromeric histone CENP-A and its chaperone HJURP could rescue centromere assembly on affected chromosomes in interphase nuclei. However, although the X. laevis chromosomes maintained centromeric CENP-A in metaphase, X. borealis chromosomes did not and also displayed ultra-thin regions containing ribosomal DNA. Both centromere assembly and morphology of X. borealis mitotic chromosomes could be rescued by inhibiting RNA polymerase I or preventing the collapse of stalled DNA replication forks. These results indicate that specific paternal centromeres are inactivated in hybrids due to the disruption of associated chromatin regions that interfere with CENP-A incorporation, at least in some cases due to conflicts between replication and transcription machineries. Thus, our findings highlight the dynamic nature of centromere maintenance and its susceptibility to disruption in vertebrate interspecies hybrids.

Earth's ecosystems are increasingly threatened by "hot drought," which occurs when hot air temperatures coincide with precipitation deficits, intensifying the hydrological, physiological, and ecological effects of drought by enhancing evaporative losses of soil moisture (SM) and increasing plant stress due to higher vapor pressure deficit (VPD). Drought-induced reductions in gross primary production (GPP) exert a major influence on the terrestrial carbon sink, but the extent to which hotter and atmospherically drier conditions will amplify the effects of precipitation deficits on Earth's carbon cycle remains largely unknown. During summer and autumn 2020, the U.S. Southwest experienced one of the most intense hot droughts on record, with record-low precipitation and record-high air temperature and VPD across the region. Here, we use this natural experiment to evaluate the effects of hot drought on GPP and further decompose those negative GPP anomalies into their constituent meteorological and hydrological drivers. We found a 122 Tg C (>25%) reduction in GPP below the 2015-2019 mean, by far the lowest regional GPP over the Soil Moisture Active Passive satellite record. Roughly half of the estimated GPP loss was attributable to low SM (likely a combination of record-low precipitation and warming-enhanced evaporative depletion), but record-breaking VPD amplified the reduction of GPP, contributing roughly 40% of the GPP anomaly. Both air temperature and VPD are very likely to continue increasing over the next century, likely leading to more frequent and intense hot droughts and substantially enhancing drought-induced GPP reductions.

ObjectivesTo examine how people living with dementia at home engage in meaningful activities, a critical component of quality of life.DesignEthnographic study design using semistructured interviews, participant-observation, and ethnographic analysis.Setting and participantsHome setting. People living with dementia were recruited through 3 geriatrics programs in the San Francisco Bay Area, along with 1 primary live-in care partner for each. Participants were purposively sampled to maximize heterogeneity of dementia severity and life experience.MeasurementsWe asked participants to self-identify and report meaningful activity engagement prior to dementia onset and during the study period using a structured questionnaire, semistructured dyadic interviews, and observed engagement in activities. Home visits were audio-recorded, transcribed, and inductively analyzed using thematic analysis.ResultsTwenty-one people living with dementia (mean age 84 years, 38% women) and 20 care partners (59 years, 85% women), including 40% professionals, 35% spouse/partners, and 15% adult children. Overarching theme: specific activities changed over time but underlying sources of meaning and identity remained stable. As dementia progressed, meaningful activity engagement took 3 pathways. Pathway 1: Activities continued with minimal adaptation when engagement demanded little functional or cognitive ability (eg, watching football on TV). Pathway 2: care partners adapted or replaced activities when engagement required greater functional or cognitive abilities (eg, traveling overseas). This pathway was associated with caregiving experience, nursing training, and strong social support structures. Pathway 3: care partners discontinued meaningful activity engagement. Discontinuation was associated with severe caregiver burden, coupled with illness, injury, or competing caregiving demands severe enough to impact their ability to facilitate activities.Conclusions and implicationsFor people living with dementia at home, underlying sources of meaning and identity remains stable despite changes in meaningful activity engagement. Many of the factors associated with adaptation vs discontinuation over time are modifiable and can serve as targets for intervention.

BackgroundOlder adults are increasingly admitted to the ICU, and those with disabilities, dementia, frailty, and multimorbidity are vulnerable to adverse outcomes. Little is known about how pre-existing geriatric conditions have changed over time.Research questionHow have changes in disability, dementia, frailty, and multimorbidity in older adults admitted to the ICU changed from 1998 through 2015?Study design and methodsMedicare-linked Health and Retirement Survey (HRS) data identifying patients 65 years of age and older admitted to an ICU between 1998 and 2015. ICU admission was the unit of analysis. Year of ICU admission was the exposure. Disability, dementia, frailty, and multimorbidity were identified based on responses to HRS surveys before ICU admission. Disability represented the need for assistance with ≥ 1 activity of daily living. Dementia used cognitive and functional measures. Frailty included deficits in ≥ 2 domains (physical, nutritive, cognitive, or sensory function). Multimorbidity represented ≥ 3 self-reported chronic diseases. Time trends in geriatric conditions were modeled as a function of year of ICU admission and were adjusted for age, sex, race or ethnicity, and proxy interview status.ResultsAcross 6,084 ICU patients, age at admission increased from 77.6 years (95% CI, 76.7-78.4 years) in 1998 to 78.7 years (95% CI, 77.5-79.8 years) in 2015 (P < .001 for trend). The adjusted proportion of ICU admissions with pre-existing disability rose from 15.5% (95% CI, 12.1%-18.8%) in 1998 to 24.0% (95% CI, 18.5%-29.6%) in 2015 (P = .001). Rates of dementia did not change significantly (P = .21). Frailty increased from 36.6% (95% CI, 30.9%-42.3%) in 1998 to 45.0% (95% CI, 39.7%-50.2%) in 2015 (P = .04); multimorbidity rose from 54.4% (95% CI, 49.2%-59.7%) in 1998 to 71.8% (95% CI, 66.3%-77.2%) in 2015 (P < .001).InterpretationRates of pre-existing disability, frailty, and multimorbidity in older adults admitted to ICUs increased over time. Geriatric principles need to be deeply integrated into the ICU setting.

BackgroundUnderstanding life expectancy can help persons with dementia, their care partners, and policymakers plan for what lies ahead. We sought to determine life expectancy and predictors of mortality for community-dwelling persons with dementia and severe disability.MethodsUsing the National Health and Aging Trends Study (NHATS) linked to Medicare claims, we identified community-dwelling respondents age 65+ who entered NHATS in 2011 with dementia and severe disability (defined as three impairments in activities of daily living), or who subsequently met criteria for dementia and then severe disability. We estimated time to death based on the timing of meeting severe disability criteria. We conducted parametric survival analyses using a Gompertz distribution to calculate risk of death and predicted median time to death. Predictors included demographic, functional, clinical characteristics, and behavioral symptoms (assessed among NHATS respondents with proxy interviews).ResultsAmong 842 community-dwelling persons with dementia and severe disability, 80.5% died during the study period. After adjusting for age and gender, overall predicted median time to death was 1.7 years (25th percentile 0.6, 75th percentile 3.8 years). Six notable characteristics were associated with shorter life expectancy: 1) older age (90+), with a predicted median time to death of 1.0 year (0.4, 2.1); 2) being bedbound, 1.1 years (0.4, 2.3); 3) being homebound, 1.2 years (0.5, 2.6); 4) having comorbid cancer, 1.2 years (0.5, 2.6); 5) unintended weight loss, 1.4 years (0.5, 3.1); and 6) comorbid depression, 1.5 years (0.6, 3.3).ConclusionsCommunity-dwelling persons with dementia and severe disability lived a median of 1.7 years. Clinicians can use the study findings to provide anticipatory guidance to patients and care partners, and policymakers to inform design of longitudinal supportive services.

Studies of genome regulation routinely use high-throughput DNA sequencing approaches to determine where specific proteins interact with DNA, and they rely on DNA amplification and short-read sequencing, limiting their quantitative application in complex genomic regions. To address these limitations, we developed directed methylation with long-read sequencing (DiMeLo-seq), which uses antibody-tethered enzymes to methylate DNA near a target protein's binding sites in situ. These exogenous methylation marks are then detected simultaneously with endogenous CpG methylation on unamplified DNA using long-read, single-molecule sequencing technologies. We optimized and benchmarked DiMeLo-seq by mapping chromatin-binding proteins and histone modifications across the human genome. Furthermore, we identified where centromere protein A localizes within highly repetitive regions that were unmappable with short sequencing reads, and we estimated the density of centromere protein A molecules along single chromatin fibers. DiMeLo-seq is a versatile method that provides multimodal, genome-wide information for investigating protein-DNA interactions.

This article explores a mentoring program for English language teachers at a university in China. At the end of the program, the teachers and mentor reported feeling transformed and set out to investigate what was transformative about their experiences by writing final reflections. Then, the teachers and mentor became the researchers, and using a case study approach, examined the reflections for mentions of change, noting themes that emerged. They also drew on other data sources in order to understand and describe these transformative elements. Four elements identified in the literature, reflection, ownership, collaboration, and personalization, emerged in a way that was customized to the group. Two additional elements also emerged, empowering encouragement and bridging the gap between theory and practice. Both the tweaking and adding of elements led to some lessons for teachers and mentors and the observation that the form of professional development is not as important as its transformative style.

This paper investigates four teachers' efforts to innovate during a semester of English language teaching at a university in China. At the end of a mentor-facilitated action research cycle, the teachers wrote their 'Story of Innovation' in order to construct deeper understandings of their experiences. These stories were examined for themes and are retold here as a collective story in order to show what 'innovation' means to the four teachers and the benefits gained from innovating. Although the teachers' understandings of innovation converged with government policies and other top-down expectations, the individual emphasis of each suggests that different teachers view innovation from the perspective of their particular context. Moreover, although each of the four saw benefits for self and their students, what emerged from their stories was how they grew from the innovation process which may best be described as gradual restructuring.

Although American Sign Language (ASL) education for second language (L2) or additional language (Ln) learners in postsecondary education has increased rapidly over the past four decades, not much is understood about the field. The scholarship of ASL education is relatively new, and little is known of the perspectives of ASL professionals in ASL education. This qualitative study included focus group discussions with 13 ASL professionals who have worked in the field of ASL education to build a better understanding of ASL education as a discipline in regard to its strengths, challenges, and directions. The results from the four focus group discussions show three emergent themes: ASL professionals, the structure of postsecondary education, and the purpose of ASL education. The challenges in developing and sustaining ASL education as a discipline are discussed, and recommendations on how ASL education as a discipline can be elevated and sustained are provided.

American Sign Language (ASL) education is a relatively new field. Thus, further research is necessary, especially regarding developing assessment tools. The goal of this study was to determine the types of assessment tools ASL level 1 teachers use in the classroom and how those teachers measure students' language progression. This study is critical because no standard ASL level 1 assessment tool measures students' skill levels to advance to the next level. The survey was created to build a better understanding of what tools ASL instructors use to assess their students' language performance. Data were collected from 93 ASL level 1 teachers. The results demonstrated a need for additional training for ASL teachers to improve their knowledge of language assessments and skills in using assessment tools, especially to support ASL students' language progress and proficiency. The results of this study provide suggestions for future assessment tools to increase the effectiveness of ASL programs across the United States.

In the University Classroom Observation Program (UCOP), middle and high school teachers spend time on campus observing science, technology, engineering, and mathematics (STEM) classes and engaging in discussions with colleagues and college instructors. The program provides a unique and reciprocal professional learning opportunity. Middle and high school teachers learn to use an observation protocol to collect data in STEM classrooms. These data serve as feedback for individual college instructors; help provide an aggregate snapshot of teaching throughout the university; and contribute to faculty professional learning opportunities, new teaching and learning initiatives, and the larger discipline-based education research (DBER) literature. UCOP offers middle and high school teachers discussion and networking opportunities to reflect on their own teaching and on ways to better prepare their students for college. Here we describe the program, articulate the benefits for stakeholders, reflect on lessons learned, and discuss important considerations for the development of similar programs. [Note: The print ISSN (1534-6104) shown on the PDF is incorrect. The correct ISSN is 1534-6102.]

BackgroundThe effects of extracranial hemorrhage (ECH), or bleeding outside the brain, are often considered transient. Yet, there are few data on the long-term and functional consequences of ECH.ObjectiveDefine the association of ECH hospitalization with functional independence and survival in a nationally representative cohort of older adults.DesignLongitudinal cohort study.Settings and participantsData from the Health and Retirement Study from 1995 to 2016, a nationally representative, biennial survey of older adults. Adults aged 66 and above with Medicare linkage and at least 12 months of continuous Medicare Part A and B enrollment.InterventionHospitalization for ECH.Main outcomes and measuresAdjusted odds ratios and predicted likelihood of independence in all activities of daily living (ADLs), independence in all instrumental activities of daily living (IADLs) and extended nursing home stay. Adjusted hazard ratio and predicted likelihood for survival.ResultsIn a cohort of 6719 subjects (mean age 77, 59% women) with average follow-up time of 8.3 years (55,767 person-years), 736 (11%) were hospitalized for ECH. ECH was associated with a 15% increase in ADL disability, 15% increase in IADL disability, 8% increase in nursing home stays, and 4% increase in mortality. After ECH, subjects became disabled and died at the same annual rate as pre-ECH but never recovered to pre-ECH levels of function. In conclusion, hospitalization for ECH was associated with significant and durable declines in independence and survival. Clinical and research efforts should incorporate the long-term harms of ECH into decision-making and strategies to mitigate these effects.

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

PurposeTo report a case of cystoid macular edema, uveitis, and vitreomacular traction in a patient with a history of breast cancer and taking anastrozole.ObservationsA 73-year-old female with a history of estrogen receptor-positive breast cancer and treatment with anastrozole presented with bilateral blurry vision, photophobia, and eye soreness. Optical coherence tomography (OCT) of both maculae revealed vitreomacular traction (VMT), an epiretinal membrane, cystoid macular edema (CME) in the right eye, and drusen without subretinal fluid bilaterally. Although later, macular OCT did show evidence of cystoid intraretinal spaces in the left eye as well. Fluorescein angiography showed bilateral petaloid leakage, bilateral slow disc leaking, as well as peripheral leakage in the right eye. Anastrozole was discontinued and, subsequent macular OCT showed release of VMT in the right eye, and eventual resolution of intraretinal cystoid spaces bilaterally.Conclusions and importanceStopping of anastrozole was associated in resolution of refractory CME in a patient on aromatase inhibitor therapy for breast cancer. It is therefore important to consider anastrozole and other aromatase inhibitor drugs as possible factors predisposing patients to the development of CME.

ContextPhthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption.ObjectiveTo examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH.DesignSecondary data analysis from a prospective cohort study.SettingPrenatal clinics in Tennessee, USA.Patients1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29.InterventionNone.Main outcome measuresPlasma pCRH at two visits (mean gestational ages 23.0 and 31.8 weeks) and change in pCRH between visits (ΔpCRH).ResultsIn weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.07, 95 %CI: 0.02, 0.11) but lower pCRH at Visit 2 (β = -0.08, 95 %CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n = 59), phthalate mixtures were associated with lower pCRH at Visit 1 (β = -0.17, 95 %CI: -0.35, 0.0006) and Visit 2 (β = -0.35, 95 %CI: -0.50, -0.19), as well as greater ΔpCRH (β = 0.16, 95 %CI: 0.07, 0.25). Among women with gestational hypertension (n = 102), phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.20, 95 %CI: 0.03, 0.36) and Visit 2 (β = 0.42; 95 %CI: 0.19, 0.64) and lower ΔpCRH (β = -0.17, 95 %CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed.ConclusionsPhthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

BackgroundIn the United States, dementia specialty centers affiliated with centers of excellence for research hold promise as locations to develop innovative, holistic care in care systems otherwise siloed by discipline or payer.ObjectiveWe conducted foundational research to inform development of patient-and family-centered palliative care interventions for dementia specialty centers.MethodsWe interviewed persons living with dementia (PLWD), current, and former care partners (CP) recruited from a specialty dementia clinic and purposively selected for variation across disease syndrome and stage. A framework method of thematic analysis included coding, analytic matrices, and pattern mapping.Results40 participants included 9 PLWD, 16 current CPs, and 15 former CPs of decedents; 48% impacted by Alzheimer's disease dementia. While help from family, support groups and adult day centers, paid caregiving, and sensitive clinical care were invaluable to PLWD, CPs, or both, these supports were insufficient to navigate the extensive challenges. Disease-oriented sources of distress included symptoms, functional impairment and falls, uncertainty and loss, and inaccessible care. Social and relational challenges included constrained personal and professional opportunities. The obligation and toll of giving or receiving caregiving were challenging. Clinical care challenges for PLWD and/or CPs included care fragmentation, insufficient guidance to inform planning and need for expert interdisciplinary clinical care at home.ConclusionFindings highlight the breadth and gravity of gaps, which surpass the disciplinary focus of either behavioral neurology or palliative care alone. Results can inform the development of novel interventions to add principles of geriatrics and neuropalliative care to dementia care.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample. Participants, drawn from the CANDLE cohort, part of the ECHO-PATHWAYS Consortium, completed study visits at 16-29 weeks (V1) and 22-39 weeks (V2) gestation (n=812). Seven urinary mono-hydroxylated PAH metabolites (OH-PAHs) were measured at V1 and serum pCRH at V1 and V2. Associations between individual log-transformed OH-PAHs (as well as two summed PAH measures) and log(pCRH) concentrations across visits were estimated using mixed effects models. Minimally-adjusted models included gestational age and urinary specific gravity, while fully-adjusted models also included sociodemographic characteristics. We additionally evaluated effect modification by pregnancy complications, fetal sex, and maternal childhood trauma history. We observed associations between 2-OH-Phenanthrene (2-OH-PHEN) and rate of pCRH change that persisted in fully adjusted models (β=0.0009, 0.00006, 0.0017), however, positive associations with other metabolites (most notably 3-OH-Phenanthrene and 1-Hydroxypyrene) were attenuated after adjustment for sociodemographic characteristics. Associations tended to be stronger at V1 compared to V2 and we observed no evidence of effect modification by pregnancy complications, fetal sex, or maternal childhood trauma history. In conclusion, we observed modest evidence of association between OH-PAHs, most notably 2-OH-PHEN, and pCRH in this sample. Additional research using serial measures of PAH exposure is warranted, as is investigation of alternative mechanisms that may link PAHs and timing of birth, such as inflammatory, epigenetic, or oxidative stress pathways.

BackgroundMaintenance of function during cancer treatment is important to older adults. Characteristics associated with pretreatment life-space mobility and changes during non-small cell lung cancer (NSCLC) treatment remain unknown.MethodsThis mixed methods cohort study recruited adults age ≥65 with advanced NSCLC starting palliative chemotherapy, immunotherapy, and/or targeted therapy from a Comprehensive Cancer Center, Veterans Affairs, and safety-net clinic. Patients completed geriatric assessments including Life-Space Assessment (LSA) pretreatment and at 1, 2, 4, and 6 months after treatment initiation. LSA scores range from 0 to 120 (greater mobility); LSA

BackgroundThe Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood.MethodsThis multicenter observational cohort study will enroll at least 600 patients

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.